Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma Journal Article


Authors: Wolchok, J. D.; Yuan, J.; Houghton, A. N.; Gallardo, H. F.; Rasalan, T. S.; Wang, J.; Zhang, Y.; Ranganathan, R.; Chapman, P. B.; Krown, S. E.; Livingston, P. O.; Heywood, M.; Riviere, I.; Panageas, K. S.; Terzulli, S. L.; Perales, M. A.
Article Title: Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma
Abstract: Immunity to self antigens on cancer is constrained by tolerance/ ignorance. DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), mediate tumor protection and regression in implantable mouse models, and dogs with spontaneous melanoma. We conducted a trial of mouse and human TYR DNA vaccines in stage III/IV melanoma patients. Eighteen human leukocyte antigen (HLA)-A*0201+ melanoma patients were randomized as follows: one group received three mouse TYR DNA injections followed by three human TYR DNA injections; the other group received the same vaccines in opposite sequence. The study was conducted at three dose levels: 100, 500, and 1,500 μg DNA/injection, administered intramuscularly (IM) every 3 weeks. Most toxicities were grade 1 injection site reactions. Seven patients developed CD8+ T-cell responses, defined by a >3 SD increase in baseline reactivity to TYR peptide in tetramer or intracellular cytokine staining (ICS) assays. There was found to be no relationship between dose, assigned schedule, and T-cell response. At a median of 42 months follow-up, median survival has not been reached. Mouse and human TYR DNA vaccines were found safe and induced CD8+ T-cell responses in 7 of 18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells.
Keywords: adult; cancer survival; clinical article; controlled study; human tissue; aged; middle aged; survival rate; human cell; thalidomide; clinical trial; fatigue; histopathology; diarrhea; drug efficacy; drug safety; side effect; cancer patient; temozolomide; cancer staging; outcome assessment; follow up; antineoplastic agent; neoplasm staging; cd8+ t lymphocyte; cd8-positive t-lymphocytes; phenotype; animals; mice; edema; melanoma; controlled clinical trial; nausea; randomized controlled trial; vomiting; hemoglobin; cell assay; immunoreactivity; alanine aminotransferase blood level; aspartate aminotransferase blood level; chill; dizziness; hyperglycemia; injection site reaction; pruritus; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; bilirubin; hypoalbuminemia; hypokalemia; hyponatremia; cytokine; double stranded dna; cellular immunity; immunotherapy; immunogenicity; effector cell; dna vaccine; drug toxicity; monophenol monooxygenase; antibodies; hla a antigen; crossover procedure; protein determination; vaccines, dna; tetramer; memory t lymphocyte; melanoma vaccine; canis familiaris; immunogenetics
Journal Title: Molecular Therapy
Volume: 15
Issue: 11
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2007-11-01
Start Page: 2044
End Page: 2050
Language: English
DOI: 10.1038/sj.mt.6300290
PUBMED: 17726460
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 24" - "Export Date: 17 November 2011" - "CODEN: MTOHC" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jedd D Wolchok
    669 Wolchok
  2. Paul Chapman
    252 Chapman
  3. Miguel-Angel Perales
    382 Perales
  4. Katherine S Panageas
    331 Panageas
  5. Isabelle C Riviere
    168 Riviere
  6. Jianda Yuan
    100 Yuan
  7. Susan Krown
    87 Krown
  8. Alan N Houghton
    273 Houghton
  9. Teresa Rasalan
    25 Rasalan
  10. Jane Jian Wang
    7 Wang
  11. Yan Zhang
    5 Zhang